tbuckley/cabot-search huggingface dataset:
Preoperative MRI pelvic floor verus preoperative urodynamics, in prediction of urinary incontinence improvement after Sacrocolpopexy: In females with Mixed Urinary Incontinence and Pelvic Organ Prolapse
Authors: A.F. Hussein, R.F. Elsayed, H.A. Hussein, A.Y. Abdelaziz, A.M. Zahran, M.S. Abdelazim
Journal: European Urology (2022)
Navigation of patients with locally advanced head and neck squamous cell carcinoma during cisplatin-based chemoradiation: A cohort study.
Authors: Gilberto de Castro, Priscila Rangel de Souza, Lenira Corsi Ruggiero Nunes, Rosilene Josefa Souza, Tamara Aparecida Vieira Dias, Nathalia dos Reis, Samira S Goes, Renata Alvim Moravia, Paulo Thadeu Fantinato Moreira, Rossana Veronica Mendoza Lopez, Maria Rita da Silva
Journal: Journal of Clinical Oncology (2022)

e18613 Background: Cisplatin(DDP)-based chemoradiation (CCR) is currently used to treat locally advanced head and neck squamous cell carcinoma (LAHNSCC), either as an exclusive modality or in the adjuvant setting. Acute, treatment-related toxicities are frequent. In this prospective cohort study, we evaluated the impact of patient (pt) navigation in multidisciplinary care by nurses on adherence to consultations and procedures, number and duration of hospital admissions, admissions to the emergency department, and treatment-related toxicities. Methods: In this prospective, uni-institutional cohort study, pts diagnosed with LAHNSCC (oral cavity, oropharynx, hypopharynx, and larynx) were consecutively included at the beginning of CCR, after informed consent. The navigation program included: (1) referral to multidisciplinary care (Nutrition, Psychology, Social Work); (2) monitoring attendance at multidisciplinary clinical visits; (3) monitoring of possible hospital and emergency admissions; and (4) diagnosis and monitoring of treatment-related toxicities, graded according to CTCAE v5.0. To observe an effect size of 0.50 with a power of 80% and a type I error of 0.05, 64 pts would be needed. Here we present the analysis of the first 26 pts included, with outcomes compared to 130 LAHNSCC pts treated with CCR at the same institution in 2019. Accrual was stopped. Results: 26 pts were included between Mar/2021 and Sep/2021, with a median age of 57 years, being 77% men, with KPS ≥ 80% in 25 pts (96%), and with a primary tumor in the oral cavity or oropharynx in 18 patients (69%). CCR was administered in the adjuvant setting in 9 pts and as an exclusive treatment in 17 pts. 10 pts (39%) experienced DDP discontinuation (mainly for toxicity) in the navigation group, compared to 67% in the control group (p = 0.008); and the duration of radiotherapy was 48d and 49d, respectively (p = 0.483). No grade 4 adverse events were observed in navigated pts. The median number of absences (any visit or treatment) was 1.0 (control) and zero (navigation, p &lt; 0.001). Admission to the emergency department occurred in 6 navigated pts (23%) as compared to 100 control pts (77%, p &lt; 0.001), while hospitalizations occurred in 1 (3.8%) and 50 (38.5%, p &lt; 0.001), respectively, lasting 4.9±9.7d and 1±0.39d (p = 0.001). Conclusions: The navigation program provided better outcomes in comparison to the control group, in terms of a lower number of missed appointments, a higher number of chemotherapy cycles administered, lower frequency of severe toxicities, lower frequency of attendance at emergency and hospitalization services, as well as reduced length of hospital stay.
Quality of life (QoL) of OSE2101 in patients with HLA-A2+ non–small cell lung cancer (NSCLC) after failure to immune checkpoint inhibitors (IO): Final data of phase 3 Atalante-1 randomized trial.
Authors: Benjamin Besse, Rosario Garcia Campelo, Manuel Cobo-Dols, Elisabeth Anne Quoix, Anne Madroszyk, Enriqueta Felip, Federico Cappuzzo, Fabrice Denis, Werner Hilgers, Giampiero Romano, Didier Debieuvre, Domenico Galetta, Editta Baldini, Santiago Viteri Ramirez, Minh Duc Phan, Wolfgang Schuette, Alona Zer, Berangere Vasseur, Rafal Dziadziuszko, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2022)

9094 Background: OSE2101 (Tedopi) is an anticancer vaccine increasing overall survival (OS) versus Standard of Care (SoC docetaxel or pemetrexed) in HLA-A2+ NSCLC patients with secondary resistance after sequential Chemo (CT)-IO (ESMO 2021 #47LBA). Here we present the QoL analysis. Methods: EGFR and ALK negative NSCLC patients who failed prior IO, ECOG PS 0-1 were randomized 2:1 to receive either OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was OS; secondary endpoints included time to ECOG PS deterioration and QoL by EORTC QLQ-C30/LC13 questionnaires at baseline and before each treatment administration until the end of treatment (EOT). Changes in QLQ-C30/LC13 scores from baseline to EoT were assessed using mixed-effects model for repeated measures (MMRM). Overall treatment effect and associated p value were estimated using MMRM. Results: 95 out of 118 (81%) patients with secondary resistance to IO completed baseline and ≥ one follow-up questionnaire. Median OS was 11.1 mo for OSE2101 vs 7.5 mo for SoC [HR 0.59; p = 0.02]. Median time to ECOG PS deterioration was 9.0 mo for OSE2101 vs 3.3 mo for SoC [HR: 0.43; p = 0.004]. Global Health Status remained stable with OSE2101 whereas it deteriorated from the 1 st cycle with SoC (p = 0.045). Most pronounced effects were observed in the physical (ability to perform activities that require physical effort; p = 0.07) and the role (ability to work and carry out daily activities; p = 0.03) functioning scores (refer table below). Patients had less mouth soreness (p = 0.01), dysphagia (p = 0.01), peripheral neuropathy (p = 0.03), alopecia (p &lt; 0.001) and fatigue (p = 0.06) with OSE2101 than with SoC. The change from baseline of dyspnea, coughing, hemoptysis, and pain were not significantly different between the 2 groups. Conclusions: In advanced HLA-A2+ NSCLC patients with secondary resistance to IO after sequential CT-IO, OSE2101 improves OS and maintains QoL vs. SoC, especially global health status, physical and role functioning scores. Patients presented fewer symptoms typically related to adverse effects of chemotherapy as compared to SoC. Clinical trial information: NCT02654587. [Table: see text]
Real-world treatment patterns and survival of U.S. patients receiving second-line anti-programmed cell death protein-1 therapy for advanced/metastatic esophageal squamous cell carcinoma.
Authors: Daniel H. Ahn, Michelle Sidel, Laura Panattoni, Naomi Sacks, Jennifer Hernandez, Reginald Villacorta
Journal: Journal of Clinical Oncology (2022)

e16042 Background: Current second-line (2L) therapies for patients (pts) with advanced/metastatic esophageal squamous cell carcinoma (adv/met ESCC), including docetaxel, paclitaxel and irinotecan, have demonstrated modest survival gains. The National Comprehensive Cancer Network added the use of anti-programmed cell death protein-1 (PD-1) therapies (e.g., pembrolizumab, nivolumab) in the 2L to their guidelines in 2020. A real-world evidence study of 2L therapy for adv/met ESCC patients reported a median (95% CI) overall survival (OS) of 201 (153-249) days but did not include recently approved anti-PD-1 agents. Other studies of 2L anti-PD-1 therapy relied on claims data without the ability to report survival. Limited studies exist for 2L ESCC real-world treatment patterns. Herein, we characterize the real-world treatment patterns and OS for a recent cohort of US pts initiating an anti-PD-1 2L therapy. Methods: Pts (≥ 18 years of age) from the United States diagnosed with adv/met ESCC and initiating an anti-PD-1 2L therapy between January 1, 2011 and February 28, 2021 were selected using the electronic health record (EHR)-derived de-identified Flatiron Health database. Pt characteristics and descriptive treatment patterns were reported. Duration of therapy (DoT; start of therapy until last administration) was computed and OS (start of therapy until death or last recorded medical activity) was estimated by the Kaplan Meier method. Results: 60 pts were included who initiated an anti-PD-1 2L therapy. At 2L initiation, the median age was 66 years, 65% were male, 53% were white, 82% had a history of smoking, and 53% had stage IV disease. The median DoT was 92 days and median OS was 303 days with variability across agents (Table) . Of the 60 pts, a total of 21 (35%) initiated 3L therapy (8 initiated an anti-PD-1; 13 initiated a non-anti-PD-1). Of the 39 (65%) pts who did not initiate a 3L therapy, 16 (41%) died within 60 days of the final 2L administration, 12 (31%) lacked 60 days of follow-up observation, and the remaining 11 (28%) patients had no further 2L treatment. Conclusions: Compared to prior real-world analyses, use of anti-PD-1 therapy in the 2L for patients with advanced/metastatic ESCC may be associated with survival gains over other approved non-anti-PD-1 therapies. However, future real-world studies are needed to directly compare PD-1 inhibitors with other 2L therapies.[Table: see text]
Prevalence of monoclonal gammopathy of undetermined significance in black South African men.
Authors: Kara Ilene Cicero, Maureen Joffe, Moosa Patel, Audrey Pentz, Paul Ruff, Suzanne Lentzsch, Siyang Leng, Codruta Chiuzan, Judith Jacobson, Timothy Rebbeck, Alfred I. Neugut
Journal: Journal of Clinical Oncology (2022)

e20032 Background: Monoclonal gammopathy of undetermined significance (MGUS) is the precursor to multiple myeloma (MM). MM disproportionately affects black individuals, but the cumulative risk of progression from MGUS to malignancy does not differ by race. Hence, the racial disparities in MM incidence appear to arise from differences in the occurrence of MGUS. Nonetheless, MGUS has been studied mainly in white populations; the study that first described the natural history of MGUS was conducted by Kyle, et al. (2006) in 97.3% white Olmsted County, Minnesota. Methods: We determined the prevalence of MGUS among black South African men &gt;30 years of age at the Chris Hani Baragwanath Academic Hospital in Johannesburg. We conducted serum protein electrophoresis (SPEP) and free light chain (FLC) quantification and used the same criteria for MGUS as the Olmsted County studies: a monoclonal protein on SPEP or an abnormal FLC-ratio plus elevation in the appropriate FLC. We also investigated the association between MGUS and various clinical and behavioral factors. Results: The prevalence of MGUS in our cohort (n=386) was 8.03% (95%CI 5.32-10.74), nearly 1.6-fold higher than in Olmsted County males. In a univariable logistic regression model, MGUS was associated with HIV status (odds ratio (OR) 2.39, 95%CI 0.95-5.51), but in the adjusted model that also included body mass index (BMI) and cigarette use, the magnitude of the association decreased to an OR of 2.17 and was not statistically significant. MGUS was associated with current (vs. never) cigarette smoking in both univariable (OR 5.2, 95%CI 1.53-24.0) and multivariable (OR 4.11, 95%CI 1.08-20.4) models. Conclusions: Not only did we find the prevalence of MGUS in black South African men to be substantially higher than in white populations, but we also report that MGUS cases are associated with potentially modifiable risk factors. Building on this pilot study, a larger study is currently underway powered to confirm the relationship between MGUS and HIV, as well as between MGUS and cigarette smoking, in a black African population inclusive of both genders. Future studies designed to evaluate genetic and matched-environmental contributions may elucidate racial disparities and facilitate the development of strategies to prevent plasma cell malignancies.[Table: see text]
HGG-54. CLK1 aberrant splicing in pediatric high-grade gliomas disrupts key oncogenic transcriptional programs
Authors: Ammar Naqvi, Brian Ennis, Run Jin, Krutika Gaonkar, Jessica Foster, Karina Conkrite, Komal Rathi, Adam Kraya, Poonam Sonawane, Peter Madsen, Phillip Storm, Adam Resnick, Jo Lynne Rokita
Journal: Neuro-Oncology (2022)

Abstract While much of the somatic coding variation underlying the oncogenic transformation of pediatric high-grade gliomas (HGGs) has been profiled, transcriptional splicing programs of these tumors remain under-explored. Here, we characterize aberrant alternative splicing in pediatric midline HGGs (n = 84). We identified 19,275 recurrent and significant (20% change from control, P &amp;lt; 0.05, FDR &amp;lt; 0.05) aberrant splicing events in 8,587 genes compared to non-diseased brainstem controls. Of those, 27% (n = 5,157) resulted in either a gain or loss of a known protein functional site within 3,294 genes. We prioritized splice variants affecting targetable kinases and found that mRNAs encoding CDC-like kinase 1 (CLK1), a known modulator of master splicing regulators, exhibit significantly increased exon 4 inclusion in midline HGGs. This leads to a gain of two known phosphorylation sites in CLK1, increased CLK1 protein expression and hyper-phosphorylation of Serine-rich splicing factors. To assess the impact of this event, we performed differential splicing and expression analyses, comparing tumors with the highest (n= 5) and lowest (n = 5) exon 4 inclusion. We discovered 3,037 genes to be differentially up-regulated in high exon 4 inclusion tumors with an enrichment of cancer-related pathways, including DNA repair, mitotic spindle, myogenesis and EMT. We next integrated these gene signatures with protein-protein interaction networks of kinase and transcription factors and show that increased CLK1 exon 4 inclusion disrupts critical regulatory networks, such as those involving FOXM1, which is implicated in cell cycle and proliferation processes. In summary, we describe aberrant splicing in pediatric HGGs as an additional mechanism that could drive tumorigenesis. Future work will focus on molecular validation and therapeutic targeting of CLK1 in available HGG models. Characterizing tumor-specific splicing variation has the potential to open new therapeutic strategies and understand mechanisms of treatment resistance in children with central nervous system tumors.
Capecitabine in pretreated metastatic pulmonary lymphoepithelioma-like carcinoma: A retrospective study.
Authors: Gavin Tin Chun Cheung, Ka Man Cheung, James Chung Hang Chow, Kwok Hung Au, Harry Ho Yin Yiu
Journal: Journal of Clinical Oncology (2022)

9093 Background: Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare disease, sharing common histological features with the undifferentiated subtype of nasopharyngeal carcinoma (NPC), and being under-represented in non-small cell lung cancer trials and clinical guidelines. While gemcitabine-based platinum doublet chemotherapy is more established in 1 st line treatment of stage IV disease, there is limited evidence for subsequent treatment strategy. Oral capecitabine is one of the active agents in metastatic NPC, and was observed to have encouraging outcomes in pulmonary LELC. Methods: All consecutive patients with pulmonary LELC in 2010 – 2019 treated in a tertiary institution were reviewed. Patients with metastatic disease who progressed after gemcitabine-based platinum doublets and treated with capecitabine were included. Capecitabine was given at 1250 mg/m 2 twice daily for 14 days followed by 7 days of rest in each cycle. Treatment response was monitored by clinical history, physical examination and imaging. Treatment was continued till drug holiday, intolerance or disease progression. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Clinical predictors for PFS and OS were analyzed using log-rank test and the Cox proportional hazard model. Results: Of the 140 LELC patients identified, 36 patients satisfied the above inclusion criteria (14 male, 22 female). Median age was 58.6 years old (range 41.5 – 75.6). All patients had an ECOG performance score of 0 or 1. 16 patients (44.4%) received 2 or more lines of prior systemic treatment. Median capecitabine cycles received was 5 (range 2 – 68). Objective response rate was 27.8% (complete response: 5.6%; partial response: 22.2%), disease control rate was 75.0%. With a median follow-up of 15.3 months (range 1.8 – 82.6), the median PFS and OS were 5.4 months (95% CI, 2.1 – 8.8) and 15.4 months (95% CI, 10.0 – 20.7) respectively. Capecitabine was generally well tolerated, with 22.2% grade 3 or above side effects, and 5.6% treatment termination due to intolerance. Bone and distant lymph node (LN) involvement were significant predictors of poorer PFS on multivariate analyses (bone: HR 3.24, 95% CI 1.44 – 7.29, p=0.004; distant LN: HR: 2.62, 95% CI 1.14 – 6.02, p=0.024). Age, sex, smoking history, number of treatment lines, and other sites of disease involvement were not significant predictors. Conclusions: This is to date the largest reported cohort of capecitabine in pre-treated metastatic pulmonary LELC. Capecitabine is effective and well tolerated, and should be considered as a treatment option after 1 st line platinum-based chemotherapy. Future studies are warranted to delineate the optimal treatment pathway of this rare disease entity.
Phase 1 study of patritumab deruxtecan (HER3-DXd; U3-1402) in combination with osimertinib in patients with advanced <i>EGFR</i>-mutated NSCLC.
Authors: Pasi A. Janne, Joseph Mostillo, Pomy Shrestha, Ruoyang Zhang, Pang-Dian Fan, Frédérique Cantero
Journal: Journal of Clinical Oncology (2022)

TPS3161 Background: Although first-line treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib improved survival in patients (pts) with advanced/metastatic EGFR-mutated ( EGFRm) non-small cell lung cancer (NSCLC), therapy after acquired resistance to osimertinib remains an unmet need. HER3 is expressed in the majority of EGFRm NSCLCs. HER3-DXd is a novel, investigational, HER3-directed antibody-drug conjugate that demonstrated preliminary single-agent clinical activity in EGFRm NSCLC. In preclinical models of EGFRm NSCLC, osimertinib increased membrane HER3 expression, improved the internalization rate of HER3-DXd, and enhanced tumor growth inhibition by HER3-DXd. Therefore, HER3-DXd with osimertinib might improve outcomes in pts with disease that progressed with osimertinib therapy. This phase 1 study (NCT04676477; U31402-A-U103) evaluates HER3-DXd in combination with osimertinib in pts with advanced EGFRm NSCLC that has progressed with first-line osimertinib therapy. Methods: This is an open-label, 2-part study of HER3-DXd in combination with osimertinib. Pts are enrolling in North America, Europe, and Asia. Dose escalation enrolls pts with locally advanced/metastatic NSCLC with an EGFR-activating mutation (exon 19 del or L858R) and progression during or after osimertinib therapy. Pts receive HER3-DXd 1.6, 3.2, 4.8, or 5.6 mg/kg intravenously (IV) every 3 weeks (Q3W) in combination with osimertinib 40 or 80 mg orally (PO) once daily (QD). Pts are enrolled in each cohort guided by safety (dose-limiting toxicities) using a Bayesian logistic regression model. Primary objectives of dose escalation are to assess safety and tolerability of the combination and identify a recommended combination dose (RCD). In dose expansion, pts will be randomized 1:1 to receive either HER3-DXd and osimertinib at the RCD (arm 1, [≈60 pts]) or HER3-DXd 5.6 mg/kg IV Q3W (arm 2, [≈60 pts]). A third arm (arm 1b, [≈60 pts]) may be added to evaluate 2 provisional RCDs of HER3-DXd + osimertinib. The primary objective of dose expansion (arms 1, 2, and 1b) is to evaluate efficacy of the combination vs that of monotherapy. The primary endpoint is objective response rate (ORR) as assessed by blinded independent central review. Other efficacy endpoints include ORR by investigator and duration of response, disease control rate, time to response, progression-free survival, and overall survival. If the RCD includes an osimertinib dose of 80 mg PO QD, ≈30 pts with advanced EGFRm NSCLC without prior treatment will be enrolled and treated at the RCD in a separate cohort; the primary objective is to assess safety and tolerability. A tumor sample after progression with osimertinib (or prior to entry) is required for pts enrolled in dose expansion for retrospective evaluation of HER3 and biomarker analyses. Clinical trial information: NCT04676477.
Tisagenlecleucel in the treatment of aggressive large B-cell lymphoma: A review of literature.
Authors: Vishal Devarkonda, Shravya Balmuri, Pramod Kumar Ponna, Sindhu Priya Devarashetty
Journal: Journal of Clinical Oncology (2022)

e19563 Background: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor T-cell therapy approved for refractory diffuse large B-cell lymphoma(DLBCL) in May 2018. However, a recently concluded phase 3 international trial showed that Tisagenlecleucel was not superior to standard salvage therapy with aggressive lymphoma that was refractory to or progressing within 12 months after first-line treatment. Also, recently the availability of long-term outcomes from earlier trials makes it an excellent time to evaluate the Sustained response(SR) and Adverse effects associated with it. Methods: A comprehensive literature search was done of Pubmed, Embase, and Cochrane. Results: We included three trials which included two multicenter trials and one case series. Schuster et al. in their single-center case series demonstrated that Tisagenlecleucel infusion in patients with refractory diffuse large B-cell lymphoma on median follow-up at 28.6 months showed Complete remission(CR): 43%; 95% CI(18-71) Sustained remission(SR): 86%; 95% CI(13 to 98), Severe cytokine-release syndrome(CRS): 18%. On further median follow-up at 60.7 months showed a CR: 46%, overall response rate(ORR): 58%, Progression-free survival(PFS): 31% (95% CI:14-51). Good recovery in humoral and cellular response. The limitation of the trial was a relatively small number of enrolled patients. JULIET trial, a more extensive multicenter phase 2 trial involving 93 patients, demonstrated that Tisagenlecleucel infusion in patients with refractory diffuse large B-cell lymphoma on 14 months median follow-up showed an ORR: 52% (95% CI, 41 to 62), CR: 40%, Partial response(PR): 12%. On further median follow-up at 40.3 months showed CR: 39%, ORR: 53·0% (95% CI 43·5–62·4). Grade 3-4 CRS: 23%. BELINDA Trial also an extensive multicenter phase 3 trial involving 322 patients which involved patients with aggressive B cell lymphoma that was refractory to or progressing within 12 months after first-line therapy showed infusion of Tisagenlecleucel with optional bridging treatment or salvage chemotherapy and autologous HSCT Showed similar Medial event-free survival(MEFS) at three months for both groups. Progression at six weeks was 25.9% in Tisagenlecleucel vs. 13.8% in the control group. Conclusions: Tisagenlecleucel infusion is shown to have a high rate of durable response in relapsed or refractory diffuse large B-cell lymphoma in adults. Long-term follow-up showing satisfactory ORR with good recovery in cellular and humoral function. However, infusion of Tisagenlecleucel with optional bridging therapy or salvage chemotherapy and autologous HSCT inpatient with aggressive B cell lymphoma that was refractory to or progressing within 12 months after first-line therapy showed Tisagenlecleucel is not superior to standard salvage therapy needing additional studies to evaluate the benefits when used as a second-line agent.